Sustained-release delayed gels

Abstract

The present invention relates to sustained-release formulations using alginate delayed gels and methods thereof.

We claim:  
     
         1 . A sustained-release delayed gel composition, comprising: 
 a) a hydrophilic polymer;    b) a biologically active agent; and    c) at least one bound polyvalent metal ion.    
     
     
         2 . The sustained-release composition of  claim 1  further comprising (d) at least one proton donor capable of freeing the bound polyvalent metal ion.  
     
     
         3 . The sustained-release composition of  claim 1  or  2  wherein the bound polyvalent metal ion is a mixture of bound and unbound polyvalent metal ion.  
     
     
         4 . The sustained-release composition of  claim 1  or  2  further comprising excipients for stabilizing the biologically active agent or the hydrophilic polymer.  
     
     
         5 . The composition of  claim 1  or  2  wherein the bound polyvalent metal ion is a salt selected from the group consisting of acetates, phosphates, lactates, tartrates, citrates, chlorides, sulfates, carbonates, hydroxides or fatty acid anions thereof.  
     
     
         6 . The composition of  claim 5  wherein the metal ion is selected from the group consisting of manganese, strontium, iron, magnesium, calcium, barium, copper, aluminum or zinc.  
     
     
         7 . The composition of  claim 6  wherein the metal ion is calcium.  
     
     
         8 . The composition of  claim 1  or  2  wherein the hydrophilic polymer is a polyanion.  
     
     
         9 . The composition of  claim 1  or  2  wherein the hydrophilic polymer is a polysaccharide.  
     
     
         10 . The composition of  claim 9  wherein the polysaccharide is an acidic polysaccharide.  
     
     
         11 . The composition of  claim 10  wherein the polysaccharide is alginate.  
     
     
         12 . The composition of  claim 11  wherein the alginate contains at least 30% guluronic acid.  
     
     
         13 . The composition of  claim 11  wherein the alginate consists of at least 0.05% by weight.  
     
     
         14 . The composition of  claim 1  or  2  wherein the biologically active agent comprises a protein.  
     
     
         15 . The composition of  claim 14  wherein the protein consists of at least 0.001 mg/ml.  
     
     
         16 . The composition of  claim 14  wherein the protein is selected from the group consisting of hematopoetic factors, colony stimulating factors, anti-obesity factors, growth factors, trophic factors, and antiinflammatory factors.  
     
     
         17 . The composition of  claim 14  wherein the protein is selected from the group consisting of leptin, G-CSF, SCF, BDNF, GDNF, NT3, GM-CSF, IL-1ra, IL2, TNF-bp, MGDF, OPG, interferons, erythropoietin, KGF, insulin and analogs or derivatives thereof.  
     
     
         18 . The composition of  claim 1  or  2  wherein the biologically active agent is a complexed biologically active agent.  
     
     
         19 . The composition of  claim 18  wherein the complexed biologically active agent is a precipitated protein.  
     
     
         20 . The composition of  claim 19  wherein the precipitated protein is a zinc leptin precipitate.  
     
     
         21 . The composition of  claim 2  wherein the proton donor is from an acid source.  
     
     
         22 . The composition of  claim 21  wherein the acid source is selected from the group consisting of buffers, esters, slowly dissolving acids or lactones.  
     
     
         23 . A method of producing a sustained-release delayed gel composition, comprising the steps of: 
 a) mixing a biologically active agent and a hydrophilic polymer in a solvent to form a first mixture; and    b) mixing to the first mixture at least one bound polyvalent metal ion to form a second mixture.    
     
     
         24 . The method of  claim 23  further comprising the step of c) mixing to the second mixture at least one proton donor capable of releasing the bound polyvalent metal ion.  
     
     
         25 . The method of  claim 23  or  24  wherein the bound polyvalent metal ion is a salt selected from the group consisting of acetates, phosphates, lactates, citrates, sulfates, tartrates, chlorides, carbonates, hydroxides or fatty acid anions thereof.  
     
     
         26 . The method of  claim 25  wherein the metal ion is selected from the group consisting of manganese, strontium, iron, magnesium, calcium, barium, copper, aluminum or zinc.  
     
     
         27 . The method of  claim 26  wherein the metal ion is calcium.  
     
     
         28 . The method of  claim 23  or  24  wherein the hydrophilic polymer is a polyanion.  
     
     
         29 . The method of  claim 23  or  24  wherein the hydrophilic polymer is a polysaccharide.  
     
     
         30 . The method of  claim 29  wherein the polysaccharide is an acidic polysaccharide.  
     
     
         31 . The method of  claim 30  wherein the polysaccharide is alginate.  
     
     
         32 . The method of  claim 31  wherein the alginate contains at least 30% guluronic acid.  
     
     
         33 . The method of  claim 31  wherein the alginate consists of at least 0.05% by weight.  
     
     
         34 . The method of  claim 23  or  24  wherein the biologically active agent comprises a protein.  
     
     
         35 . The method of  claim 34  wherein the protein consists of at least 0.001 mg/ml.  
     
     
         36 . The method of  claim 34  wherein the protein is selected from the group consisting of hematopoetic factors, colony stimulating factors, anti-obesity factors, growth factors, trophic factors, and antiinflammatory factors.  
     
     
         37 . The method of  claim 34  wherein the protein is selected from the group consisting of leptin, G-CSF, SCF, BDNF, GDNF, NT3, GM-CSF, IL-1ra, IL2, TNF-bp, MGDF, OPG, interferons, erythropoietin, KGF and analogs or derivatives thereof.  
     
     
         38 . The method of  claim 23  or  24  wherein the biologically active agent is a complexed biologically active agent.  
     
     
         39 . The method of  claim 38  wherein the complexed biologically active agent is a precipitated protein.  
     
     
         40 . The method of  claim 39  wherein the precipitated protein is a zinc leptin precipitate.  
     
     
         41 . The method of  claim 23  or  24  further comprising the step of isolating the sustained-release composition.  
     
     
         42 . The method of  claim 24  wherein the proton donor is from an acid source.  
     
     
         43 . The method of  claim 42  wherein the acid source is selected from the group consisting of buffers, esters, slowly dissolving acids or lactones.  
     
     
         44 . The sustained-release composition produced by the method of claims  23 ,  24  or  41 .  
     
     
         45 . A pharmaceutical formulation comprising the sustained-release composition according to claims  1  or  2  in a pharmaceutically acceptable carrier, diluent or adjuvant.  
     
     
         46 . The pharmaceutical formulation of  claim 45 , wherein the formulation is in a syringe.  
     
     
         47 . A method of treating an indication with a sustained-release composition according to claims  1  or  2  in a pharmaceutically acceptable carrier, diluent or adjuvant.  
     
     
         48 . A method of treatment of a disorder selected from the group consisting of excess weight, diabetes, high blood lipid level, artherial sclerosis, artherial plaque, the reduction or prevention of gall stones formation, insufficient lean tissue mass, insufficient sensitivity to insulin, and stroke, with a sustained-release composition according to claims  1  or  2  in a pharmaceutically acceptable carrier, diluent, or adjuvant wherein the biologically active agent is leptin, an analog or derivative thereof.  
     
     
         49 . A method of treating a disorder selected from the group consisting of hematopoietic cell deficiencies, infection, and neutropenia with a sustained-release composition according to claims  1  or  2  in a pharmaceutically acceptable carrier, diluent, or adjuvant wherein the biologically active agent is GCSF, an analog or derivative thereof.  
     
     
         50 . A method of treating inflammation with a sustained-release composition according to claims  1  or  2  in a pharmaceutically acceptable carrier, diluent, or adjuvant, wherein the biologically active agent is IL-1ra, an analog or derivative thereof.